Type I interferons (IFN) are critical components of the innate immune responses, in particular defense against viral infection (7, 12, 20). Paradoxically, excessive amounts of type I IFN produced from a variety of insults, including viral infection (5, 16, 22, 25) and bacterial sepsis (4, 14) can lead to significant pathology from acute inflammation (17, 21, 23). Recently, type I IFN has been shown to drive tumor necrosis factor (TNF) lethal shock (11, 28). Thus, excessive amounts of type I IFN can have negative consequences for the host, driving acute inflammation that may ultimately lead to organ failure and death (15, 25). Plato best illustrated the point: “Excess generally causes reaction, and produces a change in the opposite direction . . . ” In fact, some have called for therapeutics that neutralize type I IFNs in the treatment of inflammatory diseases, including sepsis (15, 25).
Interferons (IFNs) are proteins produced in mammals, useful as antiviral agents and for fighting tumors. Interferons (IFNs) are host defense molecules and consist of three classes, Type I, Type II and recently identified Type III. Type I IFNs including the prototypical members IFN-alpha and IFN-beta. Type I IFNs are involved in the generation of an antiviral state to help limit the spread of viruses (11) (see reference list below). The Type II class of IFNs consists solely of IFN-gamma and is predominately involved in shaping the Th1 arm of the T-cell response (10). Type III IFNs consist of IFN-lamba and have a function believed to be similar to Type I IFNs, though they signal through different receptors (3).
IFNs are potent inactivators of viral replication within infected hosts and accordingly, are key components in host defense against infection (5, 6, 13). Not surprisingly, viruses have evolved complex systems to defeat these antiviral molecules. These mechanisms include intracellular systems such as the V protein of paramyxoviruses SV5, which inhibits IFN function by targeting RIG-1-related RNA sensor MDA-5 (6). Other viruses have developed IFN-binding molecules that directly interact with IFN and neutralize its activity.
Interferons have been used to boost immune effects against several diseases, including actinic keratosis, superficial basal cell carcinoma, papilloma and external genital warts. Synthetic IFNs are also made, and administered as antiviral, antiseptic and anticarcinogenic drugs, and to treat some autoimmune diseases (e.g., Multiple sclerosis). Interferon beta-1a and interferon beta-1b are used to treat and control multiple sclerosis, an autoimmune disorder. Both hepatitis B and hepatitis C are treated with IFN-α. Interferon therapy is used as a treatment for many cancers, especially hematological malignancy; leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma. When used in the systemic therapy, IFNs are mostly administered by an intramuscular injection.
Recent findings suggest that interferon may boost the specific immune system response against the influenza virus. A flu vaccine that uses interferon as adjuvant is currently under clinical trials in the US.
One of the problems associated with IFN therapy is the large amount needed for effective treatment. For example, Interleukin-2 used to keep Hep C virus levels down in Hep C patients can result in the production of massive amounts of interferon. This over production of interferon causes severe and even life threatening adverse effects. Debilitating side effects can include flu-like symptoms, increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Other side effects are life-threatening: heart attack, stroke, enhancement of autoimmune disorder Patients might even refuse treatment with recombinant IFN-alpha and/or IL-2 because of the severe side effects.
Certain conditions and diseases are known to cause over-productions of interferon. This is true for viral infections (influenza, RSV, viral hemorrhagic fever viruses), autoimmune disorders (lupus), bacterial infections (any causing septic shock, E. coli, hemophilus influenza, Yersina Pestis, etc.
In the scientific community, there is growing recognition for the concept that neutralizing Type I interferons to negate pathogenic effects of both infectious and noninfectious (autoimmune) disease can be beneficial. However, there is currently no IFN-neutralizing therapeutic medicine or treatment that is safe and can be easily regulated. Type I IFNs constitute a constellation of molecules that include the prototypical IFN-alpha and beta as well as IFN-kappa and IFN-epsilon. In addition to these broad categories, IFN-alpha is subdivided into a multiple of IFNs which include 13 subtypes in humans. All type I IFNs signal through the type I IFN receptor. Because of the large number of type I IFNs, it is difficult to generate a product that broadly targets the entire family. Antibodies generally only bind one or type subtypes. A product that could inhibit/neutralize both IFN-alpha (and subtypes) and IFN-beta, as well as the other type I IFNs could have an advantage in terms of efficacy. Additionally, there is a large species specificity among type I IFNs, thus products that work in humans may not function effectively in mice, or other animals. This may hinder research and development. A broadly neutralizing, non-species specific product that can be used to control deleterious effects of type I IFNs in vivo is desired.